Vitamin D.sub.3 analogues have been recognized as having important biological activities. It is known, for example, that vitamin D.sub.3 analogues can be used to control calcium and phosphate metabolism.
It is also known that such analogues are useful for inducing cell differentiation and for inhibiting undesired cell proliferation. For example, it is well recognized that during normal metabolism vitamin D.sub.3 produces 1.alpha., 25-dihydroxyvitamin D.sub.3 (calcitriol) which is a potent regulator of cell differentiation and proliferation as well as intestinal calcium and phosphorus absorption and bone calcium mobilization. Calcitriol is also known to affect the immune system and this compound, as well as a variety of synthetic vitamin D3 derivatives have been used in practical, clinical chemotherapy of such diverse human illnesses as osteoporosis, cancer, immunodeficiency syndromes and skin disorders such as dermatitis and psoriasis. However, major research efforts are underway in an effort to prepare vitamin D.sub.3 analogues as drugs in which calcitropic activity is effectively separated from cell growth regulation.
Numerous references can be cited as showing prior work with respect to vitamin D.sub.3 analogues, calcitriol or the like. See, for example:
Vitamin D. Chemical, Biochemical, and Clinical Update, Proceedings of the Sixth Workshop on Vitamin D, Merano, Italy, March 1985; Norman, A. W., Schaefer, K., Grigoleit, H. G., Herrath, D. V. Eds.; W. de Gruyter; New York, 1985; Brommage, R., DeLucca, H. F., Endocrine Rev., 1985, 6, 491; Dickson, I., Nature, 1987, 325, 18; Cancela, L., Theofon, G., Norman, A. W., in Hormones and Their Actions, Part I; Cooke, B. A., King, R. J. B., Van der Molen, H. J. Eds.; Elaevier, Holland, 1988; Tsoukas, D. C., Provvedini, D. M., Manolagas, S. C., Science, (Washington, D.C.) 1984, 224, 1438; Provvedini, D. M., Tsoukas, C. D., Deftoe, L. J., Manolagas, S. C., Science, (Washington, D.C.) 1983, 221, 1181; Vitamin D. Chemical Biochemical, and Clinical Endocrinology of Calcium Metabolism, Proceedings of the Fifth Workshop on Vitamin D, Williamsburg, Va., February 1982, Norman, A. W., Schaefer, K., Herrath, D. V., Grigoleit, H. G., Eds., W. de Gruyter, New York, 1982, pp. 901-940; Calverley, M. J. in Vitamin D: Molecular., Cellular, and Clinical Endocrinology, Norman, A. W., Ed., de Gruyter; Berlin, 1988, p. 51; Calverley, M. J., Tetrahedron, 1987, 43, 4609.
Calcitriol may be structurally represented as follows: ##STR1##
The upper and lower ring portions of calcitriol may be called, for ease of reference, the C/D-ring and A-ring, respectively.
Many analogues of calcitriol have been synthesized and evaluated. Among these, all the leading candidates include the 1.alpha.-hydroxyl A-ring substituent characteristic of calcitriol, i.e. they differ in the side chain attached to the D-ring of the steroid framework. Some calcitriol analogues lacking the 1.alpha.-hydroxyl group have also been prepared, e.g. the 1.beta.-hydroxyl, 1.alpha.-fluoro and the 1-unfunctionalized (i.e. 25-hydroxyvitamin D.sub.3). However, these have been found to be much less biologically active than calcitriol and other synthesized 1.alpha.-hydroxy analogues. Accordingly, it appears to be axiomatic among workers in the field that the 1.alpha.-hydroxy group is essential for desirable biological activity. See, for example, Biochem. Biophys. Res. Commun., 97:1031 (1980); Chem. Pharm. Bull., 32:3525 (1984) and Bull. Soc. Chim. France, II:98 (1985).